Abstract Sensory deprivation from mice to man has been shown to have profound impacts on neuronal physiology, behavior and cognitive processes. Underling these changes are alterations in neuronal and non-neuronal structures. Our preliminary data shows that following one month of whisker trimming induced sensory deprivation the perineuronal net (PN), a neuron specific form of the extra cellular matrix, is significantly reduced in the barrel cortex of mice. The loss of the PN is most prominent around fast-spiking parvalbumin positive GABAergic interneurons. Converging evidence has shown that fast-spiking interneurons play a pivotal role in the closure of the developmental critical period in the visual system and their proper functioning is necessary for the proper physiological functioning of the cortex. Coincident with deprivation induced decreases in the PN we observed increases in the enzyme tissue plasminogen activator (tPA) which dissolves the PN. Under the same conditions microglia become activated, thus we propose that sensory deprivation induces microglia activation which release tPA and thus decrease the PN. In Aim 1 we will demonstrate a causal link between sensory deprivation, microglia activation and tPA release resulting in PN decreases using immunocytochemical techniques in conjunction with stereology. In Aim 2 we will focus on the physiological roll PNs have in modifying the intrinsic and synaptic properties of fast-spiking interneurons. We will employ our novel small volume incubator which allows for time dependent degradation of the PN in conjunction with dual whole-cell recordings.